The objective of this proposal is to define the mechanisms that control lymphocyte trafficking to the small and large intestines, and to characterize their roles in segregating mucosal immune responses and in targeting effector and memory cells to intestinal antigens. 1) The chemoattractant receptors CCR9 and CCR10 and their ligands, the small intestinal epithelial chemokine CCL25, and the widespread mucosal epithelial chemokine CCL28, are well-positioned to control the mucosal recruitment and dissemination of IgA antibody secreting cells (ACS). CCR9, CCR10, and dual receptor-deficient mice will be used to define the role of these receptors in the homeostatic steady-state production and distribution of IgA-secreting cells; to assess their importance in targeting antigen-specific IgA plasma cells responding to intestinal infection; and to examine critically their involvement in the recruitment of circulating IgA ASC from the blood. 2) In a challenge to current concepts of naive T cell trafficking, CDS recent thymic emigrants (RTE) are shown to home directly into the small intestines where they proliferate and differentiate in the intra-epithelial leukocyte (IEL) compartment. The role of CCR9 and CCL25 and other trafficking receptors in CDS RTE recruitment to the intestines will be assessed in homing assays, and thymic single positive mature CDS cells from monospecific T cell receptor transgenic mice will be transferred and monitored to evaluate the importance of mucosal antigen recognition to RTE activation in the gut wall. The ability of RTE to repopulate the epithelial compartment of immunodeficient mice and to contribute to IEL T-cell diversity will be evaluated. These studies have the potential to redefine current understanding of naive cell trafficking, and to identify a key role for thymic T cell export in maintaining a diverse immune repertoire at mucosal surfaces. 3) The homing of colon memory/effector T cells is poorly understood. Flow cytometry-based short term homing assays will be used to identify blast or memory T cell subsets that home well to the normal or inflamed colon, and to seek T cell populations that can home selectively to the colon vs the small intestines. Immunofluorescence and gene microarray studies will identify receptors expressed by colon-homing cells, and homing assays will define the role of these candidate adhesion and chemoattractant receptors in the selectivity of T cell subset recruitment from the blood into intestinal and other sites. Understanding lymphocyte recruitment to normal and inflamed intestines may lead to novel therapeutic approaches in inflammatory bowel diseases, as well as providing insights that can improve methods of vaccination and monitoring of mucosal immunity to HIV and other agents. ? ? ?
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